A. Field of the Invention
The present invention generally relates to processes and methods for producing, isolating, and using radiochemicals. More specifically, the methods and processes of this invention are directed to the preparation of Actinium-225 and daughters having high radiochemical and radionuclidic purity, which may be used for the preparation of alpha-emitting radiopharmaceuticals, in particular, for linkage to therapeutics such as those containing monoclonal antibodies, proteins, peptides, antisense, statin, natural products and hormones. The alpha-emitting radionuclide Actinium-225 and daughters can be used for both therapeutic and diagnostic purposes.
B. Description of Related Art
After cardiovascular disease, cancer is the second leading cause of death in the United States, accounting for one-fifth of the total mortality. Lung, prostate, and colorectal cancer are the leading cancers in men, and women are most frequently plagued by breast, lung and colorectal cancer.
Surgical removal is a frequently used therapeutic approach to treatment, but it is, obviously, invasive. Chemotherapy and radiotherapy have the advantage of being non-invasive, but have the potential disadvantage of being too non-specific. That is, killing of cancer cells is obtained with good success, yet the collateral damage can be serious. In fact, collateral damage is the major side effect of these approaches, and is often the reason patients choose to forego chemotherapy and radiotherapy in favor of surgery.
Generally, these systemic methods rely on differences between the cancer cells and the normal cells for targeting. For example, cancer cells proliferate at a faster rate than normal cells, and this difference has been exploited. The greater rate of proliferation results in a greater rate of uptake of toxic substances, as compared to the rate of uptake for normal cells. Thus, where cell toxins are introduced systemically, cancer cells take up the toxins more rapidly than normal cells, and are thereby killed to a greater extent. Obviously, this is not ideal, as any normal cell death is highly undesirable. However, the killing of normal cells by cancer therapeutic agents is a very real side effect, and as mentioned above, is a major reason patients forgo such therapy.
A number of methods have been used with success to increase the specificity of cancer targeting. These methods frequently take advantage of a some other difference between the cancer cells and the normal cells. Differences that have been exploited with good success are the structural differences between cancer cells and normal cells. These structural differences include cell surface antigens, receptors, or other surface proteins or molecules that are differentially expressed between the types of cells. Any such difference may be exploited.
For example, many tumor cells have an increased number of certain cell surface antigens as compared to normal cells. Targeting agents such as monoclonal antibodies may be used to specifically target and bind to the cell surface antigens on the tumor cells, resulting in the localization and internalization of the therapeutic agents. Specifically, for example, monoclonal antibodies such as the anti-gp160 antibody for human lung cancer (see Sugiyama et al., xe2x80x9cSelective Growth Inhibition of Human Lung Cancer Cell Lines Bearing a Surface Glycoprotein gp160 by 125I-Labeled Anti-gp160 Monoclonal Antibody,xe2x80x9d Cancer Res. 48:2768-2773 (1988), a xe2x80x9cFNT-1xe2x80x9d monoclonal antibody for human cervical carcinoma (see Chen et al., xe2x80x9cTumor Necrosis Treatment of ME-180 Human Cervical Carcinoma Model with 131I-Labeled TNT-1 Monoclonal Antibody,xe2x80x9d Cancer Res. (1989) August 15;49(16):4578-85), and antibodies against the epidermal growth factor receptor for KB carcinoma (see Aboud-Pirak et al., xe2x80x9cEfficacy of Antibodies to Epidermal Growth Factor Receptor Against KB Carcinoma In Vitro and in Nude Mice,xe2x80x9d J. National Cancer Institute 80(20):1605-1611 (1988) have been used to specifically localize tumor cells.
Various radiotherapeutic agents have also been utilized to kill tumor cells including, for example, the beta-emitters Iodine-131, Copper-67, Rhenium-186, and Yttrium-90. Beta-emitters, however, are disadvantageous because of their low specific activity, low linear energy transfer, low dose rates (allowing for cell repair of radiation damage), damage to surrounding normal tissues, and in some cases the lack of an associated imageable photon (e.g., Yttrium-90).
Alpha-emitting radionuclides are much more appropriate toxins and have the potential to more effectively treat disease. Unlike conventional systemic radiation therapy utilizing a gamma-emitter, in cell-directed radiation therapy, targeting agents seek out and attach a radioisotope to targeted cancer cells. The selective cytotoxicity offered by alpha-particle-emitting radionuclide constructs is a result of the high linear energy transfer, at least 100 times more powerful than that delivered by beta-emitting radionuclides, short particle path length (50-80 micrometers), and limited ability of cells to repair damage to DNA.
Because the radiation of alpha-emitting radionuclides only penetrates a few cell lengths in depth, there is much less of the collateral damage to healthy tissues and cells common to chemotherapy and beta- and gamma-emitting radionuclides used for radionuclide therapy. The short penetration distance allows for precise targeting of the cancer cells. Alpha-emitting radionuclides are among the most potent cytotoxic agents known and appear safe in human use.
For example, beta-emitting Iodine-131 (8.02-day half-life) is used for the treatment of non-Hodgkin""s Lymphoma, thyroid carcinoma, and other cancers. While the iodine preferentially localizes in the thyroid tissue, this treatment is still problematic because the radionuclide penetrates the tissue to a depth of 10 mm and can cause collateral damage to healthy tissues and cells. When given in sufficient doses to kill 1:91 cancer cells (up to 600 millicuries), Iodine-131 can impair or destroy bone marrow in patients, necessitating a marrow transplant. This is a very dangerous and painful process. Another beta-particle-emitting radioisotope utilized for radionuclide constructs is Yttrium-90, which because of its high energy levels, also deeply penetrates human tissue and can cause collateral damage to healthy cells or organs.
Actinium-225, Bismuth-212, Lead-212, Fermium-255, Terbium-149, Radium-223, Bismuth-213 and Astatine-211 are all alpha-emitting radionuclides that have been proposed for radionuclide therapy. Of these radionuclides, Actinium-225 (5.8 MeV alpha-emitter with a 10-day half-life) and its daughter, Bismuth-213 (46-minute half-life) may be the most efficacious. Alpha-emitting Astatine-211 also has been proposed as an appropriate alpha-emitting medical radionuclide, but would be less useful due to its short half-life (7.21 hours), which could create distribution problems.
Bismuth-213 has a shorter half-life than Actinium-225, but its physical and biochemical characteristics, its production, and its radiopharmacological characteristics, make it a good candidate for use in humans. Dr. Otto Gansow pioneered the development of alpha radioimmunotherapy, developing the linkers used to bind the monoclonal antibody to radiobismuth. (See U.S. Pat. Nos. 4,923,985, 5,286,850, 5,124,471, 5,428,154 and 5,434,287 to Gansow et al.) The alpha-emitting radioisotope Bismuth-213, in conjunction with targeting molecules, is showing promise in clinical trials using Bismuth-213 in alpha-radioimmunotherapy.
Bismuth-213 is currently being evaluated in a clinical trial for treatment of Acute Myeloblastic Leukemia (AML) and could have the potential for treatment of a range of diseases including T-Cell leukemia, non-Hodgkins lymphoma, the micrometastases associated with a range of diseases including prostate cancer, and other diseases. It has been found that Bismuth-213 could be used to halt the arteriole growth that feeds solid tumors and lung cancers. This therapy, currently used for the treatment of liquid tumors, such as leukemia, may also be useful in patients to treat solid tumors and certain other diseases, immune disorders, rheumatoid arthritis, degenerative joint diseases, and other disorders such as Kaposi""s sarcoma, an AIDS-related infectious disease. Cell-directed radiation therapy, utilizing powerful alpha-emitters for precise targeting of cancer cells, has the potential to minimize the adverse side effects associated with traditional chemotherapy or standard radiation treatments (nausea, hair loss, constipation, dry mouth, insomnia, and vomiting), potentially resulting in a preferred alternative form of disease management. Patients could be treated on an outpatient basis and the doses required would be much less than those for a beta-emitter.
Some methods for producing Actinium-225 are very dangerous, and have low yields. Using one method, Actinium-225 has been produced by the U.S. Department of Energy by extraction from long-lived (7,300 year half-life) Thorium-229. Thorium-229 is very carefully extracted in minute quantities from fissile Uranium-233, a nuclear weapons grade material produced 20-30 years ago during the Cold War from natural Thorium. For example, 5 kilograms of Uranium-233 (enough to produce 1 atomic bomb) yields only 0.5 grams of Thorium-229, or 0.1 Curies. This is only enough to treat about 10 patients. This very costly production technology, utilizing a Thorium-229 xe2x80x9ccowxe2x80x9d as an Actinium-225 generator, results in low yields of Actinium-225 because the supply of old Thorium-229 and Uranium-233 containing the extractable Thorium-229 is limited.
Even if all of the recoverable Thorium-229 in the United States that could be extracted from existing stocks of Uranium-233 were utilized, only a small amount of Actinium-225, estimated at no more than 3 curies, could be produced each month. This quantity of radionuclide is insufficient for even a number of small clinical trials and would only enable the treatment of a handful of patients who could afford the current high price charged by the U.S. Department of Energy for this radioisotope. The quantity of radioisotope required would cost in the tens of thousands of dollars.
U.S. Pat. No. 5,355,394 discloses another method for the production of effective amounts of Actinium-225 and Bismuth-213 by a very high thermal neutron flux in a nuclear reactor. However, according to the patent, years of continuous irradiation of Radium-226 in a large nuclear reactor would be necessary to produce effective amounts of Thorium-229 starting material. Thus, this process would be very slow. Another disadvantage of this production technique is that large quantities of inseparable Thorium-228 will also be produced.
This undesirable radioisotope, Thorium-228, though shorter lived, is a powerful, deeply penetrating gamma-emitter that can cause collateral damage to healthy tissues and would require a costly xe2x80x9chot cell,xe2x80x9d isolation of the patient, and considerable shielding at the medical facility where it is utilized. The Thorium-228 and 229 radioisotopes would be intimately mixed together, and it would require about 20 years in storage to decay out the Thorium-228. This would require considerable lead shielding wherever used, and would generate a great deal of radioactive waste and radon gas.
In U.S. Pat. No. 5,457,323, another method is disclosed for production of Actinium-225. This method produces radon gas, a long-lived radioactive gas, which is difficult and expensive to dispose of.
WO 99/63550 discloses another method for producing Actinium-225 from Radium-226, which involves irradiating Radium-226 with protons to produce Actinium-225. A major drawback of this method, however, is the need for a cyclotron for accelerating protons.
Thus, the major problem confronting clinicians and researchers around the world desiring to use the powerful, short lived radionuclide Actinium-225 and its Bismuth-213 daughter for treatment of cancers and other diseases is the extremely limited availability of Actinium-225 in quantities sufficient to use in clinics and for research. In addition, because of the high cost of the radionuclide, its widespread use is not currently feasible.
There is, therefore, a need in the art for new methods of production of Actinium-225.
A. Features and Advantages
This invention provides a method for the ample production of Actinium-225. Materials manufactured according to the invention are particularly useful in radioimmunotherapy to treat cancers, metastases, and micrometastases distant from the primary site.
The invention also provides a method for producing Actinium-225 at levels appropriate for commercial sales, either as a precursor, a labeled pharmaceutical, or as a coating.
The present invention provides a cost-effective method of producing large quantities of Actinium-225 which is safe and dependable, and that does not generate appreciable quantities of radioactive waste. The method also produces Actinium-225 with consistent radiochemical and radionuclidic purity.
This invention provides a reliable method for obtaining greater than 1000-millicurie quantities of Actinium-225/Bismuth-213 in  less than 5-xcexcCi Radium-225/100 xcexcCi Actinium-225 radionuclide purity via bombardment of Radium-226. The Actinium-225/Bismuth-213 has physical properties that are useful for diagnostic and therapeutic radiopharmaceuticals, particularly when used for radioimmunotherapy.
B. Summary of the Invention
The features and advantages of the present invention are provided by specific embodiments of the present invention. Such embodiments include methods of producing an isotope comprising directing electrons at a converting material coated with a coating material, the coating material having an atomic number of n; whereby interaction of the electrons with the converting material produces photons, and whereby the photons produced interact with the coating material to produce an isotope having an atomic number of nxe2x88x921.
In one embodiment, n is 226, and the coating material has an atomic number of n is Radium-226. In this embodiment, nxe2x88x921 is 225, and the isotope having an atomic number of nxe2x88x921 is Radium-225. The converting material may comprise Copper, Tungsten, Platinum and/or Tantalum. The converting material may be coated with the coating material using an electroplating procedure. The converting material may be electroplated with Nickel before being electroplated with Radium-226. Alternatively, the converting material may be electroplated with Nickel and Radium-226 simultaneously. The Radium-226 may be coated onto the converting material at a concentration of from about 80 mg/cm2 to about 160 mg/cm2.
In a method of the present invention, the electrons may be directed at the converting material coated with the coating material using an electron accelerator, wherein the electrons are in a beam. The converting material may have a thickness of from about 0.5 mm to about 1.7 mm, and the electron beam may have a current of from about 100 microampere to about 1000 microampere. The electrons may have an energy of from about 20 MeV to about 25 MeV, and the photons may have an energy of from about 10 MeV to about 25 MeV.
A method of the present invention may further include separating Actinium-225 from Radium-225 and Radium-226 using a chemical separation process.
One method of the present invention involves producing an isotope comprising directing electrons at a Tungsten plate that is electroplated with Radium-226, whereby interaction of the electrons with the Tungsten produces photons, and whereby the photons produced interact with the Radium-226 to produce Radium-225.
Other embodiments of the present invention include a target for an electron beam of an electron accelerator comprising a metal plate electroplated with Radium-226. The metal plate may have an atomic number of 30 or higher, and the metal may be selected from Tungsten, Tantalum, Platinum, and/or Copper.
The present invention also provides a metal plate coated with mixture of Radium-226 and Radium-225 and Actinium-225. The metal plate may be selected from Tungsten, Tantalum, Platinum, and Copper.
Other advantages and features of this invention will become apparent to those skilled in the art after reviewing the following technical description and additional embodiments of the present invention set forth below.